posted on 2021-11-18, 16:11authored byMarie Piantino, Masahiko Nakamoto, Michiya Matsusaki
Improving
the efficiency and selectivity of drug delivery systems
(DDS) is still a major challenge in cancer therapy. Recently, the
low transport efficiency of anticancer drugs using a nanocarrier due
to the elimination of the carriers from the blood circulation and
the blocking by tumor stromal tissues surrounding cancer cells has
been reported. Furthermore, multiple steps are required for their
intracellular delivery. We recently reported a cancer microenvironment-targeting
therapy termed molecular block (MB) which induced cancer cell death
by a pH-driven self-aggregation and cell membrane disruption at tumor
microenvironment. The MB were designed to disperse as nanoscale assemblies
in the bloodstream for efficient circulation and penetration through
the stromal tissues. When the MBs reach the tumor site, they self-assembled
in microscale aggregates on the cancer cell surfaces in response to
the cancer microenvironment and induced cancer cell death. However, in vivo study in mice showed that the MB could not efficiently
accumulate at the tumor site because slight hydrophobic aggregations
in the bloodstream might potentially be the reason for the off-target
accumulation. In this study, we optimize the hydrophilic–hydrophobic
balance of MB for avoiding the off-target accumulation and for gaining
higher sensitivity to the cancer microenvironment at weak acid condition.
Copper-free click reaction with propiolic acid was used to reduce
the hydrophobicity of the main chain and obtain higher responsive
MB at cancer microenvironment for rapid cell killing. The optimized
MB can be considered as a promising approach for an improved cancer
cell targeting.